You Make the Call
Each month in “ You Make the Call ,” we pick a challenging clinical question submitted through the Consult a Colleague program and post the expert ’ s response , but we also want to know what you would do . Send in your response to next month ’ s clinical dilemma and see how your answer matches up to the expert ’ s in the next print issue .
This month , Olatoyosi Odenike , MD , discusses a patient with a morphologic presentation suggestive of acute promyelocytic leukemia ( APL ), but with a negative PML / RARA fusion transcript result .
Clinical Dilemma :
I have a 40-year-old patient who presented with complaints of fever lasting three months . He had a few atypical cells in his peripheral smear and his bone marrow ( BM ) aspiration was morphologically suggestive of APL . PML / RAR alpha was not detected from peripheral blood . He was started on all-trans retinoic acid plus arsenic trioxide ( ATRA ). He developed cytopenia after starting hydroxyurea . How should I manage this patient ? I repeated a BM aspiration and sent the aspirate for PML / RAR alpha testing . Fluorescence in situ hybridization ( FISH ) results are pending . Does low promyelocyte count in the BM sample influence the PML / RAR alpha transcript detection ?
Expert Opinion
Olatoyosi Odenike , MD Associate Professor of Medicine Section of Hematology / Oncology The University of Chicago Medicine
APL is a medical emergency . Prompt diagnosis and treatment with ATRA , coupled with supportive care , is essential to maximize the odds of a successful outcome and reduce the risk of early mortality from complications related to disseminated intravascular coagulopathy . The hallmark of diagnosis is the demonstration of the t ( 15 ; 17 )( q24.1 ; q21.2 ) chromosomal translocation or the PML / RARA chimeric fusion gene . The PML / RARA fusion can be detected by reverse transcriptase PCR ( RT-PCR ) or by FISH . RT-PCR is generally regarded as the gold standard for diagnosis , given the heightened sensitivity and specificity and the ability to define the specific breakpoint in PML , allowing subsequent reliable monitoring of minimal residual disease . The turnaround time is variable , but in many centers these assays may take up to 48 hours or longer . Hematologists should commence ATRA as soon as a diagnosis of APL is suspected , even while genetic confirmation is pending , since the risk of early mortality from hemorrhagic complications has been correlated with delay in treatment initiation . In most cases where the morphology is consistent with APL , the diagnosis will subsequently be confirmed by the detection of the PML / RARA fusion . But what about cases where there is no evidence of a PML / RARA fusion transcript ?
Variant translocations involving the RARA gene have been described in some patients whose disease has morphologic features resembling APL , but in which there is no evidence of a PML / RARA fusion . The fusion partners involved in these variant translocations include ZBTB16 ( previously known as PLZF ) located at 11q23.2 , NUMA1 at 11q13.4 , NPM1 at 5q35.1 , and STAT5B at 17q21.2 . Other more recently described variants include PRKAR1A / RARA and FIP1L1-RARA fusions . Collectively , these variant translocations account for approximately 1 to 2 percent of APL cases . Morphologic differences can sometimes be appreciated between these cases and classic APL . For example , APL associated with the 11 ; 17 translocation resulting in the ZBTB16 / RARA fusion often lacks Auer rods , and some cases involving the NPM1 / RARA fusion have both hypergranular and hypogranular promyelocytes and an absence of Auer rods . The World Health Organization recommends that these cases be classified as APL with a variant RARA translocation .
ATRA and arsenic trioxide-based regimens have revolutionized the treatment of classic APL , turning it into a highly curable malignancy . The therapeutic implication of the diagnosis of APL with a variant RARA translocation is that some variants , including those with the STAT5B / RARA
and ZBTB16 / RARA fusions , are resistant to therapy with ATRA . The ZBTB16 / RARA variant is the most common and best studied and is also associated with resistance to arsenic trioxide . Specific management recommendations are lacking for these ATRA-resistant variants given their rarity and the consequent paucity of available evidence , but AML-like chemotherapy approaches have been proposed . By contrast , variant cases involving NPM1 / RARA , NUMA / RARA , and FIP1L1 / RARA fusions have been reported to retain sensitivity to ATRA .
Metaphase cytogenetics performed on the BM aspirate sample is instrumental in detecting variant translocations . FISH analysis using a probe that spans the RARA gene can also be useful in this regard . Ultimately , for cases of APL lacking a PML / RARA fusion , the combination of metaphase cytogenetics and FISH analysis can provide complementary information that establishes the presence of a variant translocation involving RARA , allowing therapy to be tailored accordingly .
REFERENCES
1 . Larson RA , Kondo K , Vardiman JW , et al . Evidence for a 15 ; 17 translocation in every patient with acute promyelocytic leukemia . Am J Med . 1984 ; 76:827-41 .
2 . Arber DA , Brunning RD , LeBeau MM , et al . Acute myeloid leukemia with recurrent genetic abnormalities . In : WHO Classification of tumors of haematopoietic and lymphoid tissues ( Revised 4th edition ). IARC : Lyon 2017 . Swerdlow SH , Carp E , Harris NL , et al .
3 . Zelent A , Guidez F , Melnick A , et al . Translocations of the RARα gene in acute promyelocytic leukemia . Oncogene . 2001 ; 20:7186-203 .
4 . Lo-Coco F , Avvisati G , Vignetti M , et al . Retinoic acid and arsenic trioxide for acute promyelocytic leukemia . N Engl J Med . 2013 ; 369:111-21 .
5 . Sanz MA , Grimwade D , Tallman MS , et al . Management of acute promyelocytic leukemia : recommendations from an expert panel on behalf of the European LeukemiaNet . Blood . 2009 ; 113:1875-91 .
Next Month ’ s Clinical Dilemma :
I am evaluating a 60-year-old man for cervical spine surgery ( disc disease with neurologic symptoms ) who has a prolonged prothrombin time ( PT ). He appears to have mild factor VII ( FVII ) deficiency . His bleeding history is as follows : catheter ablation for atrial fibrillation ( followed by warfarin for 10 months without bleeding ), shockwave lithotripsy ( no bleeding problems ), and tooth extractions about 30 years ago ( followed by bleeding for about 2 days , with no need for reevaluation or hemostasis ). He has no problems with minor lacerations ( e . g ., shaving ) and is physically active in taekwondo . The initial abnormality that prompted referral was a baseline PT of 15.2 seconds , international normalized ratio ( INR ) of 1.3 , with normal partial thromboplastin time . Repeat PT was 13.8 seconds , INR 1.2 , with the following factor levels : FVII 46 percent , factor II 86 percent , factor V 87 percent , and factor X 87 percent . The FVII deficiency literature suggests that surgical bleeding is rare if FVII is above 10 percent . One discussion suggested that 30 percent should be okay , but I am concerned about this being a critical bleeding site . ●
Consult a Colleague Through ASH
Consult a Colleague is a service for ASH members that helps facilitate the exchange of information between hematologists and their peers . ASH members can seek consultation on clinical cases from qualified experts in 11 categories :
• Anemias
• Hematopoietic cell transplantation
• Hemoglobinopathies
• Hemostasis / thrombosis
• Lymphomas
• Lymphoproliferative disorders
• Leukemias
• Multiple myeloma & Waldenström macroglobulinemia
• Myeloproliferative neoplasms
• Myelodysplastic syndromes
• Thrombocytopenias
Assigned volunteers (“ colleagues ”) will respond to inquiries within two business days ( either by email or phone ).
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54 ASH Clinical News May 2018